权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Neuronal ABCA7 loss of function and Alzheimer’s disease

神经元 ABCA7 功能丧失与阿尔茨海默病

基本信息

批准号：
10629715
负责人：
Takahisa Kanekiyo
金额：
$ 206.31万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629715
关键词：
ATP-Binding Cassette Transporters Abeta synthesis Acceleration Affect Age Age-associated memory impairment Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s Disease Pathway Alzheimer&apos s disease brain Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Animal Model Apolipoprotein E Bioenergetics Brain CRISPR/Cas technology Cardiolipins Cellular Membrane Cellular Stress Clinic Code Cre lox recombination system Dementia Development Elderly Endosomes Family Fatty Acids Functional disorder Genes Genetic study Heterozygote Homeostasis Human Impairment In Vitro Induced pluripotent stem cell derived neurons Knockout Mice Knowledge Label Late Onset Alzheimer Disease Link Lipids Mediating Membrane Metabolism Mitochondria Modeling Molecular Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Onset of illness Organelles Organoids Oxidation-Reduction Pathogenesis Pathogenicity Pathway interactions Phenotype Phosphatidylglycerols Play Process Property Proteins Regulation Risk Role Supplementation Susceptibility Gene Synapses Synaptosomes Terminator Codon Therapeutic Therapeutic Intervention Validation Variant aging brain amyloid pathology brain cell cell cortex cell type cognitive function early onset endoplasmic reticulum stress experimental study genetic risk factor genetic variant genome wide association study in vivo Model induced pluripotent stem cell insight lipid metabolism lipidomics lipophilicity loss of function member mitochondrial dysfunction mitochondrial membrane mouse model neuroinflammation neurotransmitter release novel oxidation premature single-cell RNA sequencing stem cell model synaptic function tau Proteins therapeutically effective transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT MAYO CLINIC JACKSONVILLE Current genetic studies indicate that susceptibility loci in late-onset Alzheimer’s disease (AD) are correlated with lipid metabolism. While ATP-binding cassette transporter A7 (ABCA7) gene variants are strongly associated with AD risk, the premature termination codon (PTC) mutations in ABCA7 significantly increases the risk for both early-onset and late-onset AD. ABCA7 belongs to the ABC transporter family regulating distribution of lipids and other lipid-related molecules across cellular membranes. Thus, exploring functions of ABCA7 in lipid metabolism should provide us important clues to determine the central pathogenic pathway for AD. While ABCA7 expression is the highest in neurons among brain cell types, our preliminary study showed that ABCA7 deficiency alters the compositions of mitochondria-related lipids and impairs mitochondria function accompanied with synaptic dysregulation in the cortical organoids and neurons derived from human induced pluripotent stem cells (iPSCs). In addition, RNA-sequencing analysis also found that pathways related to fatty acid β-oxidation in mitochondria and cellular membrane homeostasis are predominantly affected by ABCA7 deficiency in mouse brains. As lipids substantially contribute to the regulation of neuronal functions, we hypothesize that ABCA7 loss of function alters the lipid metabolism among cellular organelles, and disturbs mitochondria functions in neurons, resulting in neurodegeneration and synaptic dysfunction during aging and AD. Therefore, this proposal uniquely aims to dissect how ABCA7 deficiency impacts lipid metabolism in neurons and contributes to AD-related phenotypes including mitochondria dysregulation and synaptic dysfunction. In Aim 1, we will examine how ABCA7 deficiency influences lipid metabolism, mitochondria function, and AD-related phenotypes using iPSC-derived neurons and cortical organoids. In Aim 2, we will dissect roles of neuronal ABCA7 in AD-related phenotypes using neuron specific Abca7 knockout mouse models with or without amyloid pathology, accompanied with single cell-RNA sequencing. In Aim 3, we will explore impacts of ABCA7 deficiency on synapses, including mitochondria functions and lipid profiles, by isolating synaptosomes from conventional Abca7 knockout mice as well as neuron specific Abca7 knockout mice with or without amyloid pathology. Collectively, these studies should provide us new insights for the molecular mechanisms in which ABCA7 floss of function causes the pathogenic processes of AD by disturbing neuronal lipid homeostasis.

项目总结/文摘